Tofacitinib, an oral janus kinase inhibitor, for the treatment of rheumatoid arthritis: Safety and efficacy in open-label, long-term extension up to 6 years

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Objectives: To report tofacitinib safety, tolerability, and durability of response up to 72 months (mo) in long-term extension (LTE) studies. Methods: Data were from 2, open-label studies: A3921024 (NCT00413699 [ongoing; database unlocked as of April 2014 data cut-off]) and A3921041 (NCT00661661). Patients (pts) had RA and participated in randomised Phases (P)1/2/3 tofacitinib studies. Treatment was initiated with tofacitinib 5 or 10 mg BID as monotherapy or with background DMARDs; data for both doses ± background DMARDs were pooled. Primary endpoints: AEs and laboratory safety. Confirmed data are reported for decreased haemoglobin (HgB), neutrophil, and lymphocyte counts, and increases >50% from baseline (BL) in creatinine. Secondary endpoints: ACR responses, DAS28-4(ESR), and HAQ-DI. Safety data were included over 84 mo and efficacy up to Mo 72 (n≤29 pts, post-Mo 72). Results: 4858 pts were treated (mean [max] duration: 918 [2535] days). BL data were from index studies for 91% of pts. Total tofacitinib exposure was 12 359 ptyears (py). In total, 1747 pts (36.0%) discontinued (AEs: 882 [18.2%]; insufficient clinical response: 133 [2.7%]). Most common classes of AEs: infections and infestations (63.4%), musculoskeletal/connective tissue disorders (33.9%), and GI disorders (29.9%). Most frequently reported AEs: nasopharyngitis (16.3%), upper respiratory tract infection (14.5%), and urinary tract infection (10.3%). SAEs occurred in 23.0% of pts (incidence rate [IR] 9.9/100 py [95% confidence interval [CI]; 9.4, 10.5]) and serious infections in 7.2% (IR 2.9/100 py [95% CI; 2.6, 3.2]). Malignancies (excluding NMSC) were reported in 2.5% of pts (IR 1.0/100 py [95% CI; 0.8, 1.2]). IRs for SAEs, serious infections, and malignancies up to Mo 84 did not increase vs previously reported data (Mo 72).1 Decreased Hgb (>2g/dL change from BL or Hgb <8 g/dL) occurred in 6.1% of pts and increased aminotransferases (>3× ULN) in 1.6% (ALT) and <1.0% (AST) of pts. Moderate to severe neutropenia (absolute neutrophil count [ANC] 0.5-1.5×103/mm3) was reported in 1.3% of pts. No pts had ANC <0.5×103/mm3. Absolute lymphocyte counts <0.5×103/mm3 were reported in 1.1% of pts. Increases >50% from BL in creatinine occurred in 3.1% of pts. ACR20, ACR50 and ACR70 response rates for tofacitinib were sustained to Mo 72 (80.8%, 61.5% and 35.9%). Mean DAS28-4(ESR) was 6.29 at BL, 3.74 at LTE Mo 1 and 3.32 at Mo 72. Mean HAQ-DI score was 1.42 at BL, 0.81 at LTE Mo 1 and 0.77 at Mo 72. Conclusions: A consistent safety profile and sustained efficacy up to 72 mo was observed in pts with RA receiving tofacitinib 5 or 10 mg BID in LTE studies.